New data should help inform patient decisions

Men who underwent testosterone replacement therapy (TRT) didn't face an increased risk of venous thromboembolism (VTE) regardless of the route of administration or the exposure window in a large retrospective case-control study.

Among men who initiated testosterone within 15 days of a VTE there was a nonsignificant 10% lower risk as compared with men who had not received supplemental testosterone. The odds ratio between testosterone users and nonusers was similar for topical, transdermal, and intramuscular administration of the androgen.

In addition, expanding the testosterone exposure window 30 or 60 days also did not significantly affect the risk of VTE, Jacques Baillargeon, PhD, of the University of Texas Medical Branch at Galveston, and colleagues reported online in Mayo Clinic Proceedings.

"There are many men with clearly defined hypogonadism who may be afraid to take testosterone therapy, and there may be physicians who are reluctant to prescribe testosterone therapy based on past evidence," Baillargeon told MedPage Today. "It's important to acknowledge that for men who are truly hypogonadal, there are clear risks to not taking testosterone therapy. These men may be at increased risk for osteoporosis, sexual dysfunction, increased adiposity, decrease in lean muscle mass, and possible metabolic syndrome and cardiovascular disease."

"For men with hypogonadism, this study provides the first real evidence on this particular outcome, venous thromboembolism. It offers a basis for patients and physicians to have an evidence-based discussion about the risk-benefit assessment for this outcome."

Though not definitive, the study addresses some of the shortcomings of existing data on the topic and provides reassurance to patients and clinicians, said Alex W. Pastuszak, MD, PhD, of Baylor College of Medicine in Houston.

"Prior studies looking at this relationships have been small or have not adjusted for confounding variables, such as the use of prothrombotic medications, which the Baillargeon study does control for," said Pastuszak. "What the current study adds to the existing body of work is a large sample size with rigorously selected data, which provide a more accurate picture of the relationship between VTE and testosterone use."

In the U.S., use of TRT among middle-age and older men has more than tripled in the past decade. During the same time frame, several observational studies have suggested a potential association between TRT and VTE. Concern about a possible VTE risk prompted the FDA in 2014 to require testosterone manufacturers to add a warning to product labeling.

An association between VTE and testosterone use has biologic plausibility, Baillargeon and colleagues acknowledged. TRT increases hematocrit, blood viscosity, platelet aggregation, and the risk of polycythemia. Some case series have documented VTE in TRT-treated patients with familial and acquired thrombophilia.

Countering the negative reports, some evidence has suggested a favorable effect of testosterone on endothelial function. Additionally, two large population-based studies showed no association between endogenous testosterone and VTE.

To help resolve the conflicting evidence and inform clinical decision-making, Baillargeon and colleagues conducted a case-control study, using 2007 to 2012 data from a large commercial health insurer. During that period, more than 15 million men, age ≥40, were covered by the insurer.

Investigators identified 7,643 men who had an episode of VTE (deep vein thrombosis or pulmonary embolism) and also received at least one prescription for an anticoagulant or a vena cava filter within 60 days of VTE diagnosis. Each patient with a VTE was matched with three control patients who did not develop VTE during the study period.

Testosterone exposure was defined as at least 1 day of overlap between the most recent prescription period and the 15-day window prior to the VTE. Investigators included all doses and formulations of testosterone.

The primary analysis showed that exposure to testosterone within 15 days of a VTE was associated with an odds ratio for VTE of 0.90 versus men in the control group (95% CI 0.73-1.12). Analysis of VTE risk by route of testosterone administration yielded ORs of 0.80 to 1.15 versus the control group, all of which had overlapping confidence intervals.

Use of potentially confounding medications (prothrombotic steroids, megestrol acetate, and nonsteroidal anti-inflammatory drugs, or protective antiplatelet agents) did not change the main results.

Results for all analyses were similar for exposure windows of 15, 30, and 60 days.

Acknowledging limitations of the study, the authors noted that they excluded men who received anticoagulants in the 3 months prior to VTE or who had a VTE within the previous 12 months. Additionally, the analysis was based on receipt of a prescription for testosterone, not proof that the therapy was used. Potential inaccuracies inherent to reliance on ICD-9 codes to identify VTE might also have influenced the results.

"The findings of this study fly directly against the recent FDA mandate changes to testosterone drug labels regarding a potential increased risk of VTE, with good retrospective data across a very large sample size," Pastuszak told MedPage Today in an email. "The study acknowledges its numerous limitations, and the only definitive way to truly determine the relationship between VTE and testosterone use would be to perform a prospective, controlled study."

No one has directly examined the anti-inflammatory properties of testosterone, which might lower the risk of thrombosis, Pastuszak added.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.